Variably protease-sensitive prionopathy (VPSPr): research

Is it sporadic or genetic?

Lian and colleagues answered this with sequencing. Exome sequencing and targeted sequencing of PRNP non-coding regions were performed on genomic DNA from 67 autopsy-confirmed VPSPr patients. No potentially causal variant was identified. The common polymorphism M129V was the largest genetic risk factor, with an odds ratio of 7.0, and other variants in and near PRNP showed association only in proportion to their linkage disequilibrium with M129V, with no independent association from upstream expression quantitative trait loci. The authors state that causal variants could still hide in regions or variant classes their search did not cover, and that their data support classifying VPSPr as sporadic.

Sixty-seven cases is a large series for this disease and a small one for genetic association, so the odds ratio for M129V should be read as a strong effect measured imprecisely.

What is the biochemical signature?

Partial resistance to proteinase K, and a fragment ladder rather than the single unglycosylated band seen in CJD. Capillary electrophoresis of 29 cases identified three major fragments of about 23, 17 and 7 kDa after digestion. The 7 kDa fragment is intense, particularly in codon 129 VV cases, and is easily missed on conventional western blotting because of its size, while capillary electrophoresis detected it in all cases and gave reproducible semi-quantitative data.

Mass spectrometry has since refined the structure. Nemani and colleagues report that the three N-terminal fragments, of about 20, 17 and 7 kDa, probably share Ser97 as their N-terminal residue, that the C-terminus of the internal 7 kDa fragment is ragged, extending from Phe141 to Met154, and that the 20 and 17 kDa fragments differ only in the presence or absence of the GPI anchor. After deglycosylation the 18 kDa C-terminal fragment was not detected.

Most reported cases also lack the diglycosylated band on western blot, which is the feature a diagnostic laboratory is most likely to notice first.

How much does codon 129 change the phenotype?

Baiardi and colleagues analysed three cases, one of each codon 129 genotype, and report the polymorphism acting as a phenotypic modulator. Sensitivity of PrPSc to proteinase K ran VV greater than MV greater than MM, affecting the 19, 17 and 7 kDa fragments to different degrees. The ratio of the 19 kDa to the 7 kDa fragment was highest in the MM case and lowest in the VV case, and the relative amount of cerebral and cerebellar PrP mini-plaques on immunohistochemistry showed a similar association with genotype.

Three cases, one per genotype, cannot establish a gradient. The finding is important because VPSPr was initially described mainly in valine homozygotes, and methionine homozygous cases remain rare: a 2024 report describes the eighth such case worldwide.

What do the clinical presentations look like?

Longer courses than classic sporadic CJD, and frequently a syndrome that points somewhere else. Erro and colleagues describe two patients with progressive upper motor neuron signs, insomnia, behavioural and cognitive decline, compatible with primary lateral sclerosis plus frontotemporal dementia. Neuropathology showed spongiform encephalopathy with frontotemporal and pronounced thalamic involvement, fine synaptic PrPSc deposits, microplaques and intraneuronal aggregates; western blot showed the characteristic profile without the diglycosylated band; both were methionine homozygous with no pathogenic mutation.

A further series from Vienna and Barcelona describes two cases found at post-mortem in the setting of coexisting proteinopathy, with involvement of motor cortex and striatum in an MM case matching pyramidal and extrapyramidal signs, and places the phenotype within the frontotemporal lobar degeneration and motor neuron disease spectrum.

Why do the antemortem assays fail?

In the reported cases above, CSF RT-QuIC and 14-3-3 were negative and EEG unremarkable, with diagnosis made post-mortem. The substrate comparison quantifies it: in the panel reported by Myskiw and colleagues, end-point QuIC with the deer mouse substrate detected 3 of 5 VPSPr cases with 1 indeterminate, the same 3 of 5 with full-length hamster substrate, and 2 of 5 with the truncated hamster substrate used in second-generation RT-QuIC. VPSPr improved least of all the categories tested.

That is the practical state of play: a rapidly progressive dementia with negative prion testing, thalamic or cortical DWI change and an atypical syndrome does not exclude prion disease, and VPSPr is currently confirmed by neuropathology. Any individual case belongs with a neurologist and a reference centre; see how it is diagnosed and what to expect.

Related: sporadic CJD subtypes, BSE, variant CJD and codon 129.